A Role for the<i>Cr2</i>Gene in Modifying Autoantibody Production in Systemic Lupus Erythematosus

Wu, Xiaobo; Jiang, Ning; Deppong, Christine; Singh, Jasvinder; Dolecki, Gregory J.; Mao, Dailing; Morel, Laurence; Molina, Hector

doi:10.4049/jimmunol.169.3.1587

Cited by 69 publications

(46 citation statements)

References 38 publications

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“…Paradoxically, on certain genetic backgrounds, mice with defective expression of both Cr2 (CD21/CD35) and Fas have greater levels of lupus-like autoantibodies than do mice with either defect alone (82,83). Part of the explanation may lie in the fact that the murine Cr2 gene encodes both CR1(CD35) and CR2(CD21), two molecules with differing expression patterns and functions (83,84).…”

Section: Discussionmentioning

confidence: 99%

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Mongini

Jackson

Tolani

et al. 2003

The Journal of Immunology

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Defective expression of Fas leads to B cell autoimmunity, indicating the importance of this apoptotic pathway in eliminating autoreactive B cells. However, B cells with anti-self specificities occasionally escape such regulation in individuals with intact Fas, suggesting ways of precluding this apoptosis. Here, we examine whether coligation of the B cell Ag receptor (BCR) with the complement (C3)-binding CD21/CD19/CD81 costimulatory complex can enhance the escape of human B cells from Fas-induced death. This was warranted given that BCR-initiated signals induce resistance to Fas apoptosis, some (albeit not all) BCR-triggered events are amplified by coligation of BCR and the co-stimulatory complex, and several self Ags targeted in autoimmune diseases effectively activate complement. Using a set of affinity-diverse surrogate Ags (receptor-specific mAb:dextran conjugates) with varying capacity to engage CD21, it was established that BCR:CD21 coligation lowers the BCR engagement necessary for inducing protection from Fas apoptosis. Enhanced protection was associated with altered expression of several molecules known to regulate Fas apoptosis, suggesting a unique molecular model for how BCR:CD21 coligation augments protection. BCR:CD21 coligation impairs the generation of active fragments of caspase-8 via dampened expression of membrane Fas and augmented expression of FLIPL. This, in turn, diminishes the generation of cells that would be directly triggered to apoptosis via caspase-8 cleavage of caspase 3 (type I cells). Any attempt to use the mitochondrial apoptotic protease-activating factor 1 (Apaf-1)-dependent pathway for apoptosis (as type II cells) is further blocked because BCR:CD21 coligation promotes up-regulation of the mitochondrial antiapoptotic molecule, Bcl-2.

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Section: Discussionmentioning

confidence: 99%

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Mongini

Jackson

Tolani

et al. 2003

The Journal of Immunology

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“…Furthermore, increased CR2 expression may alter B cell responses to IFN-␣ and EBV, two alternative ligands for human CR2 that have been implicated to play a role in SLE. Finally, alterations in CR2 expression have a variety of different effects on manifestations of disease in animal models of autoimmunity (27)(28)(29)(30), suggesting that tight regulation of this receptor is critical in the induction and maintenance of tolerance. The specific effects of dysregulated expression likely depend on the cell type affected and the time in ontogeny when expression is altered.…”

Section: Discussionmentioning

confidence: 99%

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Boackle

Hanvivadhanakul

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23-42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21-43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P ‫؍‬ 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P ‫؍‬ 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5 untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus.linkage ͉ disease susceptibility ͉ antoimmunity ͉ single-nucleotide polymorphisms ͉ syntenic conservation

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“…This region on chromosome 1 is rich in genes with immunologic functions including Apcs (13), Fcgr2b (14), Cr2 (15), Daf1 (16), Pdcd-1 (17), and Ro (18). All these genes have been inactivated by gene-targeting and the knockout models displayed a variable degree of autoimmunity.…”

Section: S Ystemic Lupus Erythematosus (Sle)mentioning

confidence: 99%

Genetic Dissection of Spontaneous Autoimmunity Driven by 129-Derived Chromosome 1 Loci When Expressed on C57BL/6 Mice

Carlucci¹,

Cortés-Hernández²,

Fossati-Jimack³

et al. 2007

The Journal of Immunology

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Extensive evidence indicates that genetic predisposition is a central element in susceptibility to systemic lupus erythematosus both in humans and animals. We have previously shown that a congenic line carrying a 129-derived chromosome 1 interval on the C57BL/6 background developed humoral autoimmunity. To further dissect the contribution to autoimmunity of this 129 interval, we have created six subcongenic strains carrying fractions of the original 129 region and analyzed their serological and cellular phenotypes. At 1 year of age the congenic strain carrying a 129 interval between the microsatellites D1Mit15 (87.9 cM) and D1Mit115 (99.7 cM) (B6.129chr1b) had high levels of autoantibodies, while all the other congenic lines were not significantly different from the C57BL/6 controls. The B6.129chr1b strain displayed only mild proliferative glomerulonephritis despite high levels of IgG and C3 deposited in the kidneys. FACS analysis of the spleens revealed that the B6.129chr1b mice had a marked increase in the percentage of activated T cells associated with a significant reduction in the proportion of CD4+CD25high regulatory T cells. Moreover, this analysis showed a significantly reduced percentage of marginal zone B cells that preceded autoantibody production. Interestingly the 129chr1b-expressing bone marrow-derived macrophages displayed an impaired uptake of apoptotic cells in vitro. Collectively, our data indicate that the 129chr1b segment when recombined on the C57BL/6 genomic background is sufficient to induce loss of tolerance to nuclear Ags. These findings have important implication for the interpretation of the autoimmune phenotype associated with gene-targeted models.

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A Role for theCr2Gene in Modifying Autoantibody Production in Systemic Lupus Erythematosus

Cited by 69 publications

References 38 publications

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Role of Complement-Binding CD21/CD19/CD81 in Enhancing Human B Cell Protection from Fas-Mediated Apoptosis

Association of a common complement receptor 2 haplotype with increased risk of systemic lupus erythematosus

Genetic Dissection of Spontaneous Autoimmunity Driven by 129-Derived Chromosome 1 Loci When Expressed on C57BL/6 Mice

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